Combination therapy overcomes secondary PARPi resistance in ATM-deficient prostate cancer.

PARP inhibitors (PARPi) are approved treatments for patients with metastatic prostate cancer (mPC); tumors with homologous recombination repair (HRR) defects are particularly sensitive to this drug class. While previous work has associated ATM defects with response to PARPi, its predictive value remains controversial and the mechanisms underlying sensitivity and eventual acquired drug resistance in this setting remain unclear. To address this, we generated in vitro prostate cancer models of acquired PARPi resistance to olaparib and saruparib, a novel selective PARP1 inhibitor and pursued functional characterization and drug sensitivity studies. We found that resistant models bypass the G2/M arrest induced by PARPi in sensitive models; and display a greater reliance on the ATR-dependent response to DNA damage and replication stress, mainly through the ATR-CHK1 axis. Consistently, we demonstrate in vivo that the combination of PARPi-ATRi in resistant models restores treatment sensitivity through enhancing replication stress. Collectively, these findings highlight an interplay between ATM-ATR signaling as a key mediator of PARPi sensitivity in ATM-deficient mPC and identify a promising therapeutic combination to prolong treatment response and potentially improve patients' outcomes.